Metabolic Causes of Thrombosis in Type 2 Diabetes Mellitus

University of Maryland Baltimore (UMB)

Status and phase: Completed; Early Phase 1

Conditions: Type 2 Diabetes

Treatments: Procedure: Hyperinsulinemic hyperglycemic glucose clamp; Procedure: euinsulinemic hyperglycemic glucose clamp; Procedure: euinsulinemic euglycemic glucose clamp; Procedure: Hyperinsulinemic euglycemic glucose clamp

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00829699

HP-00044874

RFAHL04016

Details and patient eligibility

About

The purpose of this study is to learn more about why patients with diabetes have increased heart attacks, strokes and other illnesses due to blood clots causing blockage of a blood vessel. The proposed protocol will study the separate and combined effects of high glucose and high fats on certain cardiovascular responses in Type 2 DM.

Full description

Currently 75-80% of diabetes mellitus (DM) patients die due to thrombotic causes. Data from the Centers for Disease Control and Prevention released in 2000 indicated that mortality due to coronary artery disease is decreasing except in individuals with diabetes. Clearly the disordered metabolism, which includes abnormal metabolism of fats resulting in higher triglyceride and free fatty acid blood levels, occurring in diabetes predisposes these individuals to increased thrombotic events. Unless the underlying mechanisms responsible for these events can be identified, there will be an unprecedented number of diabetic patients suffering thrombotic episodes in the next 10 years.

The specific aims of this study are to determine the effects of elevated free fatty acids and hyperglycemia (high glucose)on endothelial function and thrombolytic balance in patients with type 2 diabetes, and to determine the effects of increased insulin in this setting.

Enrollment: 31 patients

Sex: All

Ages: 18 to 60 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria

• 16 Type 2 diabetic patients age 18 - 60 yrs
• 16 Non-diabetic controls age 18-60 yrs
• Body mass index >20 kg/m2
• Female volunteers of childbearing potential: negative urine pregnancy test
• Volunteers over 40 years old: an ECG with no clinically significant conduction or ischemic changes.
• For those with type 2 diabetes: HBA1C > 5.5%
• For those with type 2 diabetes: C-peptide >0.2 nmol, If C-peptide is abnormal or there is a clinical suspicion for type 1 diabetes, MODY or LADA, anti-islet cell and anti-GAD antibodies will be assessed to establish the diagnosis of type 2 diabetes vs. type 1/LADA/MODY.
• PT (time) 12.8-14.6 seconds, PTT (time) 25-38 seconds

Exclusion Criteria

• Any current disease condition that alters carbohydrate metabolism (other than type 2 DM) and/or evidence for clinically significant cardiac disease
• Uncontrolled hypertension
• Pregnancy
• Subjects unable to give voluntary informed consent
• Subjects with history of pancreatitis
• Subjects on anticoagulant drugs, anemic, or with known bleeding diseases
• Subjects with history of GI bleeding requiring treatment
• Tobacco Use
• Subjects with history of heparin-induced thrombocytopenia or heparin allergy
• Subjects with severe egg or legume (soybean) allergy
• Abnormal results following screening tests and physical examination that is clinically significant:

Medical history/Physical Exam Exclusion Criteria

• Fever greater than 38 degrees C at screening or study initiation
• Uncontrolled severe hypertension (i.e., blood pressure greater than 160/100)
• Cardiac Abnormalities (e.g. Heart Failure, Arrhythmia, Cardiomyopathy, ischemic tachycardia, S-T segment deviations, etc.,) from history or ECG testing in subjects > 40 years old.
• Diagnosed Pneumonia
• Hepatic Failure/Jaundice
• Clinically significant coagulopathy
• Renal Failure
• Acute Cerebrovascular/ Neurological deficit

Screening Laboratory Tests Exclusion Criteria according to protocol

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: Single Blind

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31 participants in 4 patient groups

1

Experimental group

Description:

Euinsulinemic (low insulin infusion) Euglycemic (normal blood glucose levels) glucose clamp with lipid (fat) infusion

Treatment:

Procedure: euinsulinemic euglycemic glucose clamp

2

Experimental group

Description:

Euinsulinemic Hyperglycemic (high glucose levels) glucose clamp with lipid infusion

Treatment:

Procedure: euinsulinemic hyperglycemic glucose clamp

3

Experimental group

Description:

Hyperinsulinemic (High dose insulin) euglycemic glucose clamp with lipid infusion

Treatment:

Procedure: Hyperinsulinemic euglycemic glucose clamp

4

Experimental group

Description:

Hyperinsulinemic hyperglycemic (high glucose level) glucose clamp with lipid infusion

Treatment:

Procedure: Hyperinsulinemic hyperglycemic glucose clamp